Exogenous IL-1Ra attenuates intestinal mucositis induced by oxaliplatin and 5-fluorouracil through suppression of p53-dependent apoptosis
Exogenous IL-1Ra attenuates intestinal mucositis induced by oxaliplatin and 5-fluorouracil through suppression of p53-dependent apoptosis
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DOI：
10.1097/cad.0000000000000142
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发表时间：
2015-01-01
影响因子：
2.3
通讯作者：
Han, Wei
中科院分区：
文献类型：
--
作者：
Wang, Xia;Gao, Jin;Han, Wei
化疗诱导的肠粘膜炎（CIM）是许多化疗药物的主要剂量限制性副作用，可导致体重减轻、腹泻甚至死亡。目前CIM的治疗是姑息性的，获益有限。白细胞介素1受体拮抗剂是白细胞介素1的天然拮抗剂。我们前期研究表明重组人白细胞介素-1受体拮抗剂（rhIL-1 Ra）对5-氟尿嘧啶化疗小鼠肠道有保护作用。在本研究中，我们进一步评估了rhIL-1 Ra对不同化疗药物及其联合诱导的CIM的治疗作用。给正常小鼠和荷瘤小鼠施用奥沙利铂（L-OHP）、5-氟尿嘧啶或其组合以诱导肠粘膜炎和死亡。rhIL-1 Ra在化疗后给药，而不是在腹泻发作后给药，显著改善小鼠存活率，减轻体重减轻，并降低腹泻的发生率、严重程度和持续时间。组织学检查显示，rhIL-1 Ra处理的小鼠具有相对完整的粘膜结构，更多的隐窝细胞增殖，以及更高的酸性粘蛋白含量比溶剂处理的小鼠。rhIL-1 Ra通过降低野生型小鼠中促凋亡蛋白的水平来抑制隐窝凋亡，但在IL-1 RI（-/-）或p53（-/-）小鼠中则不然。此外，rhIL-1 Ra在治疗化疗引起的腹泻方面与醋酸奥曲肽一样有效，但具有减少上皮细胞凋亡的优势，上皮细胞凋亡是CIM的主要原因。重要的是，肿瘤对化疗的敏感性不受rhIL-1 Ra的影响。因此，我们的数据有力地表明，rhIL-1 Ra可能是有用的治疗肠粘膜炎和改善癌症患者化疗的生活质量。抗癌药物26：35-45（C）2014年沃尔特斯Kluwer健康垂直酒吧利平科特威廉姆斯&威尔金斯。
Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect of many chemoagents, resulting in weight loss, diarrhea, and even death. The current treatments for CIM are palliative and have limited benefit. Interleukin-1 receptor antagonist is a natural antagonist of interleukin-1. Our previous studies showed the protective effect of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on the intestine in mice after 5-fluorouracil chemotherapy. In this study, we further evaluated rhIL-1Ra in the treatment of CIM induced by different chemoagents and their combination. Normal as well as tumor-bearing mice were administered oxaliplatin (L-OHP), 5-fluorouracil, or their combination to induce intestinal mucositis and mortality. rhIL-1Ra administered after the chemotherapy, but not after the onset of diarrhea, significantly improved mouse survival, attenuated body weight loss, and reduced the incidence, severity, and duration of diarrhea. Histological examination showed that rhIL-1Ra-treated mice had a relatively intact mucosa structure, more proliferating crypt cells, and higher acid mucin content than the vehicle-treated mice. rhIL-1Ra suppressed crypt apoptosis by reducing the levels of proapoptotic proteins in wild-type, but not in IL-1RI(-/-) or p53(-/-) mice. In addition, rhIL-1Ra was as effective as octreotide acetate in the treatment of chemotherapy-induced diarrhea, but with the advantage of reducing the epithelial apoptosis, the major cause of CIM. Importantly, the tumor sensitivity to chemotherapy was not affected by rhIL-1Ra. Thus, our data strongly suggest that rhIL-1Ra may be useful for the treatment of intestinal mucositis and improving the quality of life for cancer patients on chemotherapy. Anti-Cancer Drugs 26: 35-45 (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.